Publications by authors named "Somdet Srichairatanakool"

62 Publications

Anti-Malarial and Anti-Lipid Peroxidation Activities of Deferiprone-Resveratrol Hybrid in -Infected Mice.

Biology (Basel) 2021 Sep 14;10(9). Epub 2021 Sep 14.

Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand.

Iron is essential for all organisms including fast-dividing malarial parasites. Inversely, iron chelators can inhibit parasite growth through the inhibition of DNA synthesis and can ameliorate oxidative cell damage. Deferiprone (DFP)-resveratrol (RVT) hybrid (DFP-RVT) is a lipophilic anti-oxidative, iron-chelating agent that has displayed potent neuroprotective and anti-plasmodium activities in vitro. The goal of this work was to investigate the inhibitory effects of DFP-RVT on parasite growth and oxidative stress levels during malaria infections. Mice were intraperitoneally infected with and orally administered with DFP, DFP-RVT and pyrimethamine for 4 d. The percentage of parasitemia was determined using Giemsa's staining/microscopic examination. Amounts of the lipid-peroxidation product, thiobarbituric acid-reactive substance (TBARS), were determined in both plasma and liver tissue. In our findings, DFP-RVT exhibited a greater potent inhibitory effect and revealed an improvement in anemia and liver damage in infected mice than DFP. To this point, the anti-malarial activity was found to be associated with anti-RBC hemolysis and the liver weight index. In addition, plasma and liver TBARS levels in the DFP-RVT-treated mice were lower than those in DFP-treated mice. Thus, DFP-RVT could exert anti-plasmodium, anti-hemolysis and anti-lipid peroxidation activities to a better degree than DFP in -infected mice.
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http://dx.doi.org/10.3390/biology10090911DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8468766PMC
September 2021

Antioxidant Effects of Anthocyanin-Rich Riceberry™ Rice Flour Prepared Using Dielectric Barrier Discharge Plasma Technology on Iron-Induced Oxidative Stress in Mice.

Molecules 2021 Aug 17;26(16). Epub 2021 Aug 17.

Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand.

Redox-active iron generates reactive oxygen species that can cause oxidative organ dysfunction. Thus, the anti-oxidative systems in the body and certain dietary antioxidants, such as anthocyanins, are needed to control oxidative stress. We aimed to investigate the effects of dielectric barrier discharge (DBD) plasma technology in the preparation of Riceberry™ rice flour (PRBF) on iron-induced oxidative stress in mice. PRBF using plasma technology was rich in anthocyanins, mainly cyanidine-3-glucoside and peonidine-3-glucoside. PRBF (5 mg AE/mg) lowered WBC numbers in iron dextran (FeDex)-loaded mice and served as evidence of the reversal of erythrocyte superoxide dismutase activity, plasma total antioxidant capacity, and plasma and liver thiobarbituric acid-reactive substances in the loading mice. Consequently, the PRBF treatment was observed to be more effective than NAC treatment. PRBF would be a powerful supplementary and therapeutic antioxidant product that is understood to be more potent than NAC in ameliorating the effects of iron-induced oxidative stress.
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http://dx.doi.org/10.3390/molecules26164978DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8399969PMC
August 2021

Chemical Analysis, Toxicity Study, and Free-Radical Scavenging and Iron-Binding Assays Involving Coffee () Extracts.

Molecules 2021 Jul 8;26(14). Epub 2021 Jul 8.

Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand.

We aimed to analyze the chemical compositions in Arabica coffee bean extracts, assess the relevant antioxidant and iron-chelating activities in coffee extracts and instant coffee, and evaluate the toxicity in roasted coffee. Coffee beans were extracted using boiling, drip-filtered and espresso brewing methods. Certain phenolics were investigated including trigonelline, caffeic acid and their derivatives, gallic acid, epicatechin, chlorogenic acid (CGA) and their derivatives, -coumaroylquinic acid, -coumaroyl glucoside, the rutin and syringic acid that exist in green and roasted coffee extracts, along with dimethoxycinnamic acid, caffeoylarbutin and cymaroside that may be present in green coffee bean extracts. Different phytochemicals were also detected in all of the coffee extracts. Roasted coffee extracts and instant coffees exhibited free-radical scavenging properties in a dose-dependent manner, for which drip coffee was observed to be the most effective ( < 0.05). All coffee extracts, instant coffee varieties and CGA could effectively bind ferric ion in a concentration-dependent manner resulting in an iron-bound complex. Roasted coffee extracts were neither toxic to normal mononuclear cells nor breast cancer cells. The findings indicate that phenolics, particularly CGA, could effectively contribute to the iron-chelating and free-radical scavenging properties observed in coffee brews. Thus, coffee may possess high pharmacological value and could be utilized as a health beverage.
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http://dx.doi.org/10.3390/molecules26144169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8304909PMC
July 2021

Identifying a Deferiprone-Resveratrol Hybrid as an Effective Lipophilic Anti-Plasmodial Agent.

Molecules 2021 Jul 3;26(13). Epub 2021 Jul 3.

Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand.

Malaria i a serious health problem caused by spp. that can be treated by an anti-folate pyrimethamine (PYR) drug. Deferiprone (DFP) is an oral iron chelator used for the treatment of iron overload and has been recognized for its potential anti-malarial activity. Deferiprone-resveratrol hybrids (DFP-RVT) have been synthesized to present therapeutic efficacy at a level which is superior to DFP. We have focused on determining the lipophilicity, toxicity and inhibitory effects on growth and the iron-chelating activity of labile iron pools (LIPs) by DFP-RVT. According to our findings, DFP-RVT was more lipophilic than DFP ( < 0.05) and nontoxic to blood mononuclear cells. Potency for the inhibition of was PYR > DFP-RVT > DFP in the 3D7 strain (IC = 0.05, 16.82 and 47.67 µM, respectively) and DFP-RVT > DFP > PYR in the K1 strain (IC = 13.38, 42.02 and 105.61 µM, respectively). The combined treatment of DFP-RVT with PYR additionally enhanced the PYR activity in both strains. DFP-RVT dose-dependently lowered LIP levels in PRBCs and was observed to be more effective than DFP at equal concentrations. Thus, the DFP-RVT hybrid should be considered a candidate as an adjuvant anti-malarial drug through the deprivation of cellular iron.
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http://dx.doi.org/10.3390/molecules26134074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8271877PMC
July 2021

Protection of Iron-Induced Oxidative Damage in Neuroblastoma (SH-SY5Y) Cells by Combination of 1-(N-Acetyl-6-aminohexyl)-3-hydroxy-2-methylpyridin-4-one and Green Tea Extract.

Bioinorg Chem Appl 2021 20;2021:5539666. Epub 2021 Apr 20.

Oxidative Stress Cluster, Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand.

Iron is a crucial trace element and essential for many cellular processes; however, excessive iron accumulation can induce oxidative stress and cell damage. Neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease, have been associated with altered iron homoeostasis causing altered iron distribution and accumulation in brain tissue. This study aims to investigate the protective effect of 1-(acetyl-6-aminohexyl)-3-hydroxy-2-methylpyridin-4-one (CM1) in combination with green tea extract (GTE) on iron-induced oxidative stress in neuroblastoma (SH-SY5Y) cells. Cells were cultured in medium with or without ferric chloride loading. Their viability and mitochondrial activity were assessed using MTT and JC-1 staining methods. Levels of the cellular labile iron pool (LIP), reactive oxygen species (ROS), and lipid-peroxidation products were determined using calcein acetoxymethyl ester, 2',7'-dichlorohydrofluorescein diacetate, and TBARS-based assays, respectively. The viability of iron-loaded cells was found to be significantly increased after treatment with CM1 (10 M) for 24 h. CM1 co-treatment with GTE resulted in a greater protective effect than their monotherapy. Combination of CM1 and GTE also reduced mitochondrial disruption and LIP content and ROS and TBARS production. In conclusion, the combination of CM1 and GTE exhibits protection against iron-induced oxidative stress in neuroblastoma cells.
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http://dx.doi.org/10.1155/2021/5539666DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8079199PMC
April 2021

Correlation of hepcidin and serum ferritin levels in thalassemia patients at Chiang Mai University Hospital.

Biosci Rep 2021 02;41(2)

Division of Hematology and Oncology, Department of Pediatrics, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand.

Hepcidin is a key iron-regulatory hormone, the production of which is controlled by iron stores, inflammation, hypoxia and erythropoiesis. The regulation of iron by hepcidin is of clinical importance in thalassemia patients in which anemia occurs along with iron overload. The present study aimed to evaluate the correlation between serum hepcidin and ferritin levels in thalassemia patients. This cross-sectional study investigated 64 patients with thalassemia; 16 β-thalassemia major (BTM), 31 β-thalassemia/hemoglobin (Hb) E (BE), and 17 Hb H + AE Bart's disease (Hb H + AE Bart's). The levels of serum hepcidin and ferritin, and Hb of the three groups were measured. The median values of serum ferritin and Hb were significantly different among the three groups, whereas serum hepcidin values were not observed to be significantly different. The correlation of the serum hepcidin and ferritin levels was not statistically significant in any of the three groups of thalassemia patients with BTM, BE, or Hb H + AE Bart's (r = -0.141, 0.065 and -0.016, respectively). In conclusion, no statistically significant correlations were observed between serum hepcidin with any variables including serum ferritin, Hb, age, labile plasma iron (LPI), and number of blood transfusion units among the three groups of thalassemia patients. Likely, the regulation of hepcidin in thalassemia patients is affected more by erythropoietic activity than iron storage.
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http://dx.doi.org/10.1042/BSR20203352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7886874PMC
February 2021

Analgesic, anti-inflammatory and anti-ulcer properties of Thai Perilla frutescence fruit oil in animals.

Biosci Rep 2021 01;41(1)

Oxidative Stress Cluster, Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.

Perilla frutescens fruit oil (PFO) is rich in α-linolenic acid (ALA) and exhibits biological activities. We aimed to investigate analgesic, anti-inflammatory and anti-ulcer activities of PFO and PFO-supplemented soybean milk (PFO-SM) in animal models. Analgesic activity was assessed in acetic acid-induced writhing in mice, while anti-inflammatory activity was performed in ethyl phenylpropiolate (EPP)-induced ear edema and carrageenan-induced hind paw edema in rats. Anti-ulcer effects were conducted in water immersion stress, HCl/ethanol and indomethacin-induced gastric ulcer in rats. Distinctly, PFO, containing 6.96 mg ALA and 2.61 mg LA equivalence/g, did not induce acute toxicity (LD50 > 10 mL/kg) in mice. PFO (2.5 and 5 mL/kg) and PFO-SM (0.05 mL PFO equivalence/kg) inhibited incidences of writhing (16.8, 18.0 and 32.3%, respectively) in acetic acid-induced mice. In addition, topical applications of PFO (0.1 and 1 mL/ear) significantly inhibited EPP-induced ear edema (59.3 and 65.7%, respectively) in rats, while PFO-SM slightly inhibited ear edema (25.9%). However, PFO and PFO-SM did not inhibit carrageenan-induced hind paw edema in rats. Indeed, PFO (2.5 and 5 mL/kg) significantly inhibited gastric ulcers in rats that induced by water immersion stress (92.4 and 96.6%, respectively), HCl/ethanol (74.8 and 73.3%, respectively) and indomethacin (68.8 and 88.9%, respectively), while PFO-SM did not. PFO displayed potent analgesic, anti-inflammatory and anti-ulcer properties, while PFO-SM exerted only analgesic properties. Thus, Thai PFO and its functional drink offer potential benefits in treatment of analgesic, inflammatory diseases and gastric ulcer.
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http://dx.doi.org/10.1042/BSR20203166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823181PMC
January 2021

Anti-Platelet Aggregation and Anti-Cyclooxygenase Activities for a Range of Coffee Extracts ().

Molecules 2020 Dec 22;26(1). Epub 2020 Dec 22.

Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand.

Coffee is rich in caffeine (CF), chlorogenic acid (CGA) and phenolics. Differing types of coffee beverages and brewing procedures may result in differences in total phenolic contents (TPC) and biological activities. Inflammation and increases of platelet activation and aggregation can lead to thrombosis. We focused on determining the chemical composition, antioxidant activity and inhibitory effects on agonist-induced platelet aggregation and cyclooxygenase (COX) of coffee beverages in relation to their preparation method. We prepared instant coffee and brewed coffee beverages using drip, espresso, and boiling techniques. Coffee extracts were assayed for their CF and CGA contents using HPLC, TPC using colorimetry, platelet aggregation with an aggregometer, and COX activity using ELISA. The findings have shown all coffee extracts, except the decaffeinated types, contained nearly equal amounts of CF, CGA, and TPC. Inhibitory effects of coffee extracts on platelet aggregation differed depending on the activation pathways induced by different agonists. All espresso, drip and boiled coffee extracts caused dose dependent inhibition of platelet aggregation induced by ADP, collagen, epinephrine, and arachidonic acid (ARA). The most marked inhibition was seen at low doses of collagen or ARA. Espresso and drip extracts inhibited collagen-induced platelet aggregation more than purified caffeine or CGA. Espresso, boiled and drip coffee extracts were also a more potent inhibitors of COX-1 and COX-2 than purified caffeine or CGA. We conclude that inhibition of platelet aggregation and COX-1 and COX-2 may contribute to anti-platelet and anti-inflammatory effects of espresso and drip coffee extracts.
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http://dx.doi.org/10.3390/molecules26010010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7792775PMC
December 2020

Early detection of ventricular dysfunction by tissue Doppler echocardiography related to cardiac iron overload in patients with thalassemia.

Int J Cardiovasc Imaging 2021 Jan 29;37(1):91-98. Epub 2020 Jul 29.

Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.

Cardiac T2* MRI is used as a gold standard for cardiac iron quantification in patients with transfusion-dependent thalassemia (TDT). We hypothesized that left ventricular (LV) diastolic dysfunction would reflect the severity of iron overload and can serve as an early detection of cardiac iron deposits. A study was conducted on all patients with TDT. Hemoglobin, serum ferritin and non-transferrin bound iron, together with a complete echocardiography and cardiac T2* MRI, were performed on all patients. Seventy-seven patients with TDT were enrolled (median age 14 years). In the patient group with a mean serum ferritin of > 2500 ng/mL during the past 12 months, there were more patients with severe cardiac iron deposits than in the group with a mean serum ferritin of ≤ 2500 ng/mL. Diastolic dysfunction was absent in all patients with a serum ferritin of < 1000 ng/mL. All patients with cardiac T2* ≤ 20 ms had grade III LV diastolic dysfunction. However, twenty-one percent of patients with cardiac T2* > 20 ms had LV diastolic dysfunction. The differences observed in pulmonary vein atrial reversal duration and mitral A-wave (PVAR-MVA) duration ≥ - 1 ms and an E/E' ratio ≥ 11 were proven to be the associated factors with the cardiac T2* ≤ 20 ms. Increased PVAR-MVA duration and increased E/E' ratio reliably reflected a severe iron overload, according to a cardiac T2* in patients with TDT. LV diastolic dysfunction can occur prior to severe cardiac iron deposition. Tissue Doppler echocardiography has the potential for the early detection of cardiac involvement in patients with TDT .
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http://dx.doi.org/10.1007/s10554-020-01949-8DOI Listing
January 2021

Ubiquitin activation is essential for schizont maturation in Plasmodium falciparum blood-stage development.

PLoS Pathog 2020 06 22;16(6):e1008640. Epub 2020 Jun 22.

Malaria Parasitology Laboratory, The Francis Crick Institute, London, United Kingdom.

Ubiquitylation is a common post translational modification of eukaryotic proteins and in the human malaria parasite, Plasmodium falciparum (Pf) overall ubiquitylation increases in the transition from intracellular schizont to extracellular merozoite stages in the asexual blood stage cycle. Here, we identify specific ubiquitylation sites of protein substrates in three intraerythrocytic parasite stages and extracellular merozoites; a total of 1464 sites in 546 proteins were identified (data available via ProteomeXchange with identifier PXD014998). 469 ubiquitylated proteins were identified in merozoites compared with only 160 in the preceding intracellular schizont stage, suggesting a large increase in protein ubiquitylation associated with merozoite maturation. Following merozoite invasion of erythrocytes, few ubiquitylated proteins were detected in the first intracellular ring stage but as parasites matured through trophozoite to schizont stages the apparent extent of ubiquitylation increased. We identified commonly used ubiquitylation motifs and groups of ubiquitylated proteins in specific areas of cellular function, for example merozoite pellicle proteins involved in erythrocyte invasion, exported proteins, and histones. To investigate the importance of ubiquitylation we screened ubiquitin pathway inhibitors in a parasite growth assay and identified the ubiquitin activating enzyme (UBA1 or E1) inhibitor MLN7243 (TAK-243) to be particularly effective. This small molecule was shown to be a potent inhibitor of recombinant PfUBA1, and a structural homology model of MLN7243 bound to the parasite enzyme highlights avenues for the development of P. falciparum specific inhibitors. We created a genetically modified parasite with a rapamycin-inducible functional deletion of uba1; addition of either MLN7243 or rapamycin to the recombinant parasite line resulted in the same phenotype, with parasite development blocked at the schizont stage. Nuclear division and formation of intracellular structures was interrupted. These results indicate that the intracellular target of MLN7243 is UBA1, and this activity is essential for the final differentiation of schizonts to merozoites.
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http://dx.doi.org/10.1371/journal.ppat.1008640DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7332102PMC
June 2020

Characterization of two siderophores produced by Bacillus megaterium: A preliminary investigation into their potential as therapeutic agents.

Biochim Biophys Acta Gen Subj 2020 10 19;1864(10):129670. Epub 2020 Jun 19.

Institute of Pharmaceutical Science, King's College London, London SE1 9NH, United Kingdom. Electronic address:

Background: Microorganisms produce siderophores in order to scavenge iron from the environment and this study focuses on the characterization of the two siderophores secreted by Bacillus megaterium. The general biological properties and pharmacokinetics following oral application of these compounds are reported.

Methods: Under optimized culture conditions, the siderophores were harvested, purified by chromatography and identified using LC-MS and NMR. Two dihydroxamate siderophores were isolated, schizokinen (MW = 420) and schizokinen imide (MW = 402).

Results: Both compounds demonstrate strong antioxidant activity and were found to be relatively nontoxic to both human hepatocellular carcinoma (Huh7) and peripheral blood mononuclear cells. The siderophores possess a strong affinity for iron(III) and decrease the levels of the labile iron pool (LIP) in iron-loaded cells in a concentration-dependent manner. Schizokinen, was detected as both the free siderophore and the iron complex in the plasma and urine of rats after oral gavage.

Conclusions: However, the bioavailability was low and thus schizokinen, like deferoxamine, has no potential as an orally active iron chelator for the treatment of systemic iron overload.

General Significance: By virtue of the high affinity of schizokinen for tribasic metals, this siderophore does have considerable potential for the chelation of gallium(III) and the development of clinical diagnostic reagents.
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http://dx.doi.org/10.1016/j.bbagen.2020.129670DOI Listing
October 2020

Phytosterol, Lipid and Phenolic Composition, and Biological Activities of Guava Seed Oil.

Molecules 2020 May 27;25(11). Epub 2020 May 27.

Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand.

Plant seeds have been found to contain bioactive compounds that have potential nutraceutical benefits. Guava seeds () are by-products in the beverage and juice industry; however, they can be utilized for a variety of commercial purposes. This study was designed to analyze the phytochemicals of the -hexane extract of guava seed oil (GSO), to study its free-radical scavenging activity, and to monitor the changes in serum lipids and fatty acid profiles in rats that were fed GSO. The GSO was analyzed for phytochemicals using chromatographic methods. It was also tested for free-radical scavenging activity in hepatoma and neuroblastoma cells, and analyzed in terms of serum lipids and fatty acids. GSO was found to contain phenolic compounds (e.g., chlorogenic acid and its derivatives) and phytosterols (e.g., stimasterol, β-sitosterol and campesterol), and exerted radical-scavenging activity in cell cultures in a concentration-dependent manner. Long-term consumption of GSO did not increase cholesterol and triglyceride levels in rat serum, but it tended to decrease serum fatty acid levels in a concentration-dependent manner. This is the first study to report on the lipid, phytosterol and phenolic compositions, antioxidant activity, and the hepato- and neuro-protection of hydrogen peroxide-induced oxidative stress levels in the GSO extract.
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http://dx.doi.org/10.3390/molecules25112474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7321134PMC
May 2020

Extracts of Thai Perilla frutescens nutlets attenuate tumour necrosis factor-α-activated generation of microparticles, ICAM-1 and IL-6 in human endothelial cells.

Biosci Rep 2020 05;40(5)

Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand.

Elevation of endothelial microparticles (EMPs) play an important role in the progression of inflammation-related vascular diseases such as cardiovascular diseases (CVDs). Thai perilla (Perilla frutescens) nutlets are rich in phenolic compounds and flavonoids that exert potent antioxidant and anti-inflammatory effects. We found that the ethyl acetate (EA) and ethanol (Eth) extracts of Thai perilla nutlets contain phenolic compounds such as luteolin, apigenin, chryseoriol and their glycosides, which exhibit antioxidant activity. The goal of the present study was to investigate the effects of the extracts on endothelial activation and EMPs generation in tumour necrosis factor-α (TNF-α)-induced EA.hy926 cells. We found that TNF-α (10 ng/ml) activated EA.hy926 cells and subsequently generated EMPs. Pre-treatment with the extracts significantly attenuated endothelial activation by decreasing the expression of the intracellular adhesion molecule-1 (ICAM-1) in a dose-dependent manner. Only the Eth extract showed protective effects against overproduction of interleukin-6 (IL-6) in the activated cells. Furthermore, the extracts significantly reduced TNF-α-enhanced EMPs generation in a dose-dependent manner. In conclusion, Thai perilla nutlet extracts, especially the Eth extract, may have potential to protect endothelium against vascular inflammation through the inhibition of endothelial activation and the generation of endothelial microparticles (EMPs).
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http://dx.doi.org/10.1042/BSR20192110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7260356PMC
May 2020

Consumption of a green tea extract-curcumin drink decreases blood urea nitrogen and redox iron in β-thalassemia patients.

Food Funct 2020 Jan;11(1):932-943

Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand.

The most important cause of death in β-thalassemia major patients is organ dysfunction due to iron deposits. Non-transferrin bound iron (NTBI), labile plasma iron (LPI) and labile iron pool are redox-active forms of iron found in thalassemia. Iron chelation therapy is adopted to counteract the resulting iron overload. Extracts of green tea (GTE) and curcumin exhibit iron-chelating and antioxidant activities in iron-loaded cells and β-thalassemic mice. We have used our GTE-CUR drink to investigate the potential amelioration of iron overload and oxidative stress in transfusion-dependent β-thalassemia (TDT) patients. The patients were enrolled for a control group without and with GTE-CUR treatments (17.3 and 35.5 mg EGCG equivalent). Along with regular chelation therapy, they were daily administered the drink for 60 d. Blood samples were collected at the beginning of the study and after 30 d and 60 d for biochemical and hematological tests. Interestingly, we found a decrease of blood urea nitrogen levels (P < 0.05), along with a tendency for a decrease of NTBI and LPI, and a delay in increasing lipid-peroxidation product levels in the GTE-CUR groups. The findings suggest that GTE-CUR could increase kidney function and diminish redox-active iron in iron overloaded β-thalassemia patients.
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http://dx.doi.org/10.1039/c9fo02424gDOI Listing
January 2020

Synthesis and iron coordination properties of schizokinen and its imide derivative.

Dalton Trans 2019 Nov;48(46):17395-17401

Institute of Pharmaceutical Science, King's College London, London, SE1 9NH, UK.

The iron(iii) affinity constants for schizokinen and its imide derivative are reported for the first time. Surprisingly, schizokinen possesses a higher affinity for iron(iii) than desferrioxamine B; log KFeIII (FeL), 36.2 and 30.6, respectively. This increase in value is associated with the substitution of one hydroxamate function by an α-hydroxycarboxylate grouping. By virtue of the similarity of siderophore-iron(iii) complexes and siderophore-gallium(iii) complexes, schizokinen (which is a Gram positive siderophore) has potential for 68Ga PET-based imaging.
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http://dx.doi.org/10.1039/c9dt02731aDOI Listing
November 2019

Deferiprone and efonidipine mitigated iron-overload induced neurotoxicity in wild-type and thalassemic mice.

Life Sci 2019 Dec 31;239:116878. Epub 2019 Oct 31.

Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand; Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand; Department of Oral Biology and Diagnostic Sciences, Faculty of Dentistry, Chiang Mai University, Chiang Mai, 50200, Thailand. Electronic address:

Aims: We previously demonstrated that iron-overload in non-thalassemic rats induced neurotoxicity and cognitive decline. However, the effect of iron-overload on the brain of thalassemic condition has never been investigated. An iron chelator (deferiprone) provides neuroprotective effects against metal toxicity. Furthermore, a T-type calcium channels blocker (efonidipine) effectively attenuates cardiac dysfunction in thalassemic mice with iron-overload. However, the effects of both drugs on brain of iron-overload thalassemia has not been determined. We hypothesize that iron-overload induces neurotoxicity in Thalassemic and wild-type mice, and not only deferiprone, but also efonidipine, provides neuroprotection against iron-overload condition.

Main Methods: Mice from both wild-type (WT) and β-thalassemic type (HT) groups were assigned to be fed with a standard-diet or high-iron diet containing 0.2% ferrocene/kg of diet (HFe) for 4 months consecutively. After three months of HFe, 75-mg/kg/d deferiprone or 4-mg/kg/d efonidipine were administered to the HFe-fed WT and HT mice for 1 month.

Key Findings: HFe consumption caused an equal impact on circulating iron-overload, oxidative stress, and inflammation in WT and HT mice. Brain iron-overload and iron-mediated neurotoxicity, such as oxidative stress, inflammation, glial activation, mitochondrial dysfunction, and Alzheimer's like pathologies, were observed to an equal degree in HFe fed WT and HT mice. These pathological conditions were mitigated by both deferiprone and efonidipine.

Significance: These findings indicate that iron-overload itself caused neurotoxicity, and T-type calcium channels may play a role in this condition.
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http://dx.doi.org/10.1016/j.lfs.2019.116878DOI Listing
December 2019

Linoleic acid-rich guava seed oil: Safety and bioactivity.

Phytother Res 2019 Oct 22;33(10):2749-2764. Epub 2019 Jul 22.

Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.

Guava (Psidium guajava) is a widely consumed fruit and has been commercialized in markets. The seeds are by-products of the processing procedures performed by the commercial guava juice industry. They are considered a nutritional resource that has been poorly utilized as they contain essential fatty acids such as linoleic acid (LA) and phenolics in abundance. In the study, guava seed oil (GSO) was used, which was obtained by hexane extraction of guava seeds to determine composition and test toxicity, cell migration, cancer cell viability, and plasmodium growth. GSO was found to be relatively nontoxic to normal hepatocytes and peripheral blood mononuclear cells, with mice for 14 days showing median lethal dose (LD ) > 10 mg/kg and rats for up to 90 days. Surprisingly, the oil inhibited the proliferation of the human erythroleukemic cells in a dose-dependent manner with the half maximal inhibitory concentration values of 155 and 137 μg/ml at 24 and 48 hr, respectively. Importantly, GSO at 500 μg/ml was found to increase the degree of migration of keratinocytes (HaCaT). These observations suggest that edible P. guajava seed oil, which is abundant with linoleic acid and antioxidants, can promote skin wound healing and inhibit the proliferation of leukemic cells.
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http://dx.doi.org/10.1002/ptr.6449DOI Listing
October 2019

A chemically characterized ethanolic extract of Thai Perilla frutescens (L.) Britton fruits (nutlets) reduces oxidative stress and lipid peroxidation in human hepatoma (HuH7) cells.

Phytother Res 2019 Aug 29;33(8):2064-2074. Epub 2019 May 29.

Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand.

Perilla frutescens is cultivated in East Asian countries including Thailand, and the nutlets (single-seeded fruits) are used as traditional and medicinal food. Perilla nutlets extracted by ethyl acetate (EA), 80% ethanol (Eth), and hot water (HW) sequentially were chemically characterized using high-resolution accurate liquid chromatography-mass spectrometry with the main compounds detected assigned as rosmarinic acid and derivatives of the flavones apigenin and luteolin, with the more diverse chemical composition observed with the Eth extract. All extracts showed dose-dependent free-radical scavenging activity, with the Eth extract the most potent (IC  = 3.43 mg/ml for ABTS scavenging and 0.27 mg/ml for DPPH scavenging). The Eth extract also inhibited AAPH-induced hemolysis (IC  = 0.07 mg/ml) more potently than did the HW (IC  = 0.38 mg/ml) and EA extracts (IC  = 1.63 mg/ml). An MTT test revealed all the extracts were noncytotoxic at concentrations up to 200 μg/ml. Only the Eth and EA extracts showed protective effects against the generation of reactive oxygen species and lipid peroxidation in FeCl -induced HuH7 cells in a dose-dependent manner. Our findings suggest the Eth extract of Thai perilla nutlets, containing rosmarinic acid and flavones and their derivatives, may have potential to provide protection against oxidative stress in hepatic disorders.
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http://dx.doi.org/10.1002/ptr.6396DOI Listing
August 2019

Decrement in Cellular Iron and Reactive Oxygen Species, and Improvement of Insulin Secretion in a Pancreatic Cell Line Using Green Tea Extract.

Pancreas 2019 May/Jun;48(5):636-643

Department of Haematology, University College London, London, United Kingdom.

Objectives: We have investigated the efficacy of mono- and combined therapy with green tea extract (GTE) in mobilizing redox iron, scavenging reactive oxygen species (ROS), and improving insulin production in iron-loaded pancreatic cells.

Methods: Rat insulinoma pancreatic β-cells were iron-loaded using culture medium supplemented with either fetal bovine serum or ferric ammonium citrate and treated with various doses of GTE for epigallocatechin-3-gallate (EGCG) equivalence and in combination with iron chelators. Cellular iron, ROS, and secretory insulin were measured.

Results: The rat insulinoma pancreatic cells took up iron from fetal bovine serum more rapidly than ferric ammonium citrate. After treatment with GTE (0.23-2.29 μg EGCG equivalent), cellular levels of iron and ROS were dose dependently decreased. Importantly, secretory insulin levels were increased nearly 2.5-fold with 2.29 μg of EGCG equivalent GTE, indicating a recovery in insulin production.

Conclusions: Green tea EGCG ameliorated oxidative damage of iron-loaded β-cells by removing redox iron and free radicals and attenuating insulin production. The impact can result in the restoration of pancreatic functions and an increase in insulin production. Green tea extract exerts iron-chelating, free-radical scavenging, and pancreato-protective effects in the restoration of β-cell functions, all of which we believe can increase insulin production in diabetic β-thalassemia patients.
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http://dx.doi.org/10.1097/MPA.0000000000001320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6553981PMC
February 2020

Anti-inflammatory and Antioxidant Activities of the Extracts from Leaves and Stems of Polygonum odoratum Lour.

Antiinflamm Antiallergy Agents Med Chem 2019 ;18(1):45-54

Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai-50200, Thailand.

Background: Polygonum odoratum is an indigenous vegetable that has been used as a favoring agent and also used as a Thai traditional medicine to treat flatulence.

Objective: To analyze active ingredients, total phenolic and total flavonoid contents, antiinflammatory and antioxidant activities from leaf and stem extracts of P. odoratum.

Methods: Leaves and stems were dried and extracted by using methanol, dichloromethane and water for obtaining Methanolic Leaf Extract (MLE), Methanolic Stem Extract (MTE), Dichloromethane Leaf Extract (DLE), Dichloromethane Stem Extract (DTE), Water Leaf Extract (WLE) and Water Stem Extract (WTE). The extracts were quantified for total phenolic and total flavonoid contents by spectrophotometry and active compounds were analyzed by using GC-MS. Antioxidant activity was determined by ABTS and DPPH radicals scavenging assays. Anti-inflammatory activity was tested by the inhibition of nitric oxide production in RAW 264.7 macrophage cells induced by lipopolysaccharide.

Results: The DLE exhibited the most potent anti-inflammatory effect by inhibiting nitric oxide production in a concentration-dependent manner (IC50 = 53.75±0.72 µg/mL). MLE exhibited strong antioxidant activity and contained the highest concentration of phenolic compounds (52.59±0.58 mg gallic acid equivalent/g extract) and flavonoid (19.97+0.11 mg quercetin equivalent/g extract). E-15-Heptadecenal and 3, 7, 11, 15-tetramethyl-2- hexadecen-1-ol were found predominantly in the methanol extracts.

Conclusion: The leaf extract of P. odoratum showed potent anti-inflammatory and antioxidant activities, mediated by DLE and MLE, respectively.
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http://dx.doi.org/10.2174/1871523017666181109144548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6446461PMC
October 2019

Green tea extract modulates oxidative tissue injury in beta-thalassemic mice by chelation of redox iron and inhibition of lipid peroxidation.

Biomed Pharmacother 2018 Dec 12;108:1694-1702. Epub 2018 Oct 12.

Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand. Electronic address:

Iron overload in patients with β-thalassemia can cause oxidative organ dysfunction. Iron chelation along with antioxidant supplementation can ameliorate such complications and prolong lives. Green tea extract (GTE) rich in epigallocatechin-3-gallate (EGCG) exhibits anti-oxidation and iron chelation properties in β-knockout thalassemic (BKO) mice diagnosed with iron overload. We investigated the effects of GTE and deferiprone (DFP) alone in combination with one another, and upon the levels of redox-active iron, lipid-peroxidation product, insulin and hepcidin in BKO mice. A state of iron overload was induced in the mice via a trimethylhexanoyl-ferrocene supplemented (Fe) diet for 3 months, and the mice were treated daily with either: DFP (50 mg/kg), DFP (50 mg/kg) plus GTE (50 mg EGCG equivalent/kg), or GTE alone for 2 months. Plasma non-transferrin bound iron (NTBI), malondialdehyde (MDA), alanine aminotransferase (ALT), aspartate aminotransferase (AST), hepcidin and insulin; tissue iron and MDA were measured. DFP, GTE and GTE + DFP effectively decreased plasma MDA (p < 0.05), NTBI and ALT, and increased plasma hepcidin and insulin. All the treatments also reduced iron accumulation and MDA production in both the pancreas and liver in the mice. However, the combination therapy demonstrated no advantages over monotherapy. The findings suggest GTE improved liver and pancreatic β-cell functions in iron-overloaded β-thalassemia mice by diminishing redox iron and free radicals, while inhibiting lipid peroxidation. Consequently, there are indications that GTE holds significant potential for clinical use.
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http://dx.doi.org/10.1016/j.biopha.2018.10.017DOI Listing
December 2018

Effects of the iron chelator deferiprone and the T-type calcium channel blocker efonidipine on cardiac function and Ca regulation in iron-overloaded thalassemic mice.

Cell Calcium 2018 06 6;72:18-25. Epub 2018 Feb 6.

Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand; Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand; Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, 50200, Thailand. Electronic address:

Although disturbance of cardiac Ca regulation is involved in the pathophysiology of iron-overload cardiomyopathy, the obvious mechanisms involved in the dysregulation of iron-induced cardiac Ca are unclear. Moreover, the roles of the iron chelator deferiprone and the T-type calcium channel blocker efonidipine on cardiac intracellular Ca transients and Ca regulatory proteins in thalassemic mice are still unknown. We tested the hypothesis that treatment with either deferiprone or efonidipine attenuated cardiac Ca dysregulation and led to improved left ventricular (LV) function in iron-overloaded thalassemic mice. Wild-type (WT) mice and β-thalassemic (HT) mice were fed with either a normal diet (ND) or a high iron-diet (FE) for 90 days. Then, the FE-fed mice were treated with either deferiprone (75 mg/kg/day) or efonidipine (4 mg/kg/day) for 30 days. ND-fed HT mice had an increase in T-type calcium channels (TTCC) and an increased level of sarcoplasmic reticulum Ca-ATPase (SERCA), compared with ND-fed WT mice. Chronic iron feeding led to an increase in TTCC and expression of SERCA proteins in FE-fed WT mice. Moreover, chronic iron overload led to increased plasma non-transferrin bound iron (NTBI) and cardiac iron deposition, impaired cardiac intracellular Ca transients including decreased intracellular Ca transient amplitude, rising rate and decay rate, as well as impaired LV function as indicated by a decreased %LV ejection fraction (%LVEF) in both WT and HT mice. Our findings showed that treatment with either deferiprone (DFP) or efonidipine (EFO) showed similar benefits in reducing plasma NTBI and cardiac iron deposition, and improving %LVEF from 84.3 (WT) to 89.3 (DFP) and 89.2 (EFO) treatment; and from 84.2 (HT) to 88.8 (DFP) and 89.5 (EFO) treatment, however there was no improvement in the regulation of cardiac Ca in iron-overloaded thalassemic mice. These findings provide the understanding of the effects of these drugs on the iron-overloaded heart in thalassemic mice and suggest that an alternative intervention that could improve calcium regulation under this condition is needed to improve the therapeutic outcome. Moreover, whether the benefits of the TTCC blocker is via its inhibition of the TTCC alone or together with its ability to chelate iron are still unclear and need further investigation.
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http://dx.doi.org/10.1016/j.ceca.2018.01.004DOI Listing
June 2018

Combined iron chelator and T-type calcium channel blocker exerts greater efficacy on cardioprotection than monotherapy in iron-overload thalassemic mice.

Eur J Pharmacol 2018 Mar 31;822:43-50. Epub 2018 Jan 31.

Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand; Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand; Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, Thailand. Electronic address:

Although both iron chelators and T-type calcium channel (TTCC) blockers have been shown to exert cardioprotection by decreasing cardiac iron deposition and reducing left ventricular (LV) dysfunction via different channels in iron-overloaded rodent models, the cardioprotective effects of combined iron chelator and TTCC blocker treatment in thalassemic mice has not been investigated. We hypothesized that a combined iron chelator and TTCC blocker exerts better cardioprotection than monotherapy by decreasing cardiac iron accumulation, apoptosis and oxidative stress. An iron-overload condition was induced in heterozygous β thalassemic (HT) mice and wild-type (WT) mice by high iron diet consumption (FE) for 3 months. Then, the iron chelator deferiprone (DFP), the TTCC blocker efonidipine (Efo), and combined DFP plus Efo were fed via oral gavage for 1 month whilst the high iron diet was continued. LV function, heart rate variability (HRV), apoptosis and cardiac iron accumulation were determined. Chronic iron-overload in mice led to increased cardiac iron deposition, oxidative stress, apoptosis, and impaired LV function and HRV. Although DFP and Efo showed similar cardioprotective efficacy, the combined DFP plus Efo therapy exerted greater efficacy in reducing cardiac iron deposition and cellular apoptosis than either of the monotherapies in iron-overload thalassemic mice.
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http://dx.doi.org/10.1016/j.ejphar.2018.01.015DOI Listing
March 2018

A combination of an iron chelator with an antioxidant exerts greater efficacy on cardioprotection than monotherapy in iron-overload thalassemic mice.

Free Radic Res 2018 Jan 19;52(1):70-79. Epub 2017 Dec 19.

a Cardiac Electrophysiology Research and Training Center, Faculty of Medicine , Chiang Mai University , Chiang Mai , Thailand.

Many recent studies have shown that antioxidant compounds decrease cardiac oxidative stress, decrease cardiac iron deposition, and improve cardiac dysfunction in iron-overload induced cardiomyopathy in animal models. Interestingly, a therapy including the combination of the iron chelator deferiprone (DFP) plus the antioxidant N-acetylcysteine (NAC) has been shown to significantly decrease oxidative stress and restore heart and brain function in iron-overloaded rats. However, the cardioprotective effects of this combined DFP and NAC treatment in thalassemic mice have not been investigated. We hypothesised that the combination of DFP and NAC exerts better cardioprotection than monotherapy via decreasing cardiac iron accumulation, oxidative stress, and apoptosis in thalassemic mice. The iron-overload condition was induced in heterozygous β HT and wild-type mice by instigating high iron diet consumption (FE) for three months. Then, iron chelator DFP (75 mg/kg/day twice a day), antioxidant NAC (100 mg/kg/day once a day), and combined DFP plus NAC were fed via oral gavage for one month with continuous iron feeding. Left ventricular (LV) function, heart rate variability (HRV), apoptosis, and cardiac iron accumulation were determined. Chronic iron-overload in mice led to increased cardiac iron deposition, oxidative stress, apoptosis, and impaired LV function and HRV. Although DFP and NAC showed similar cardioprotective efficacy, combined DFP plus NAC exerted greater efficacy in reducing both cardiac iron deposition and cellular apoptosis than monotherapy. In conclusion, combined iron chelator and NAC treatment exert the greatest cardioprotective efficacy when compared with either of the monotherapies in iron-overload thalassemic mice.
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http://dx.doi.org/10.1080/10715762.2017.1414208DOI Listing
January 2018

Prevalence of low bone mass among adolescents with nontransfusion-dependent hemoglobin E/β-thalassemia and its relationship with anemia severity.

Pediatr Blood Cancer 2018 Jan 12;65(1). Epub 2017 Aug 12.

Thalassemia Center and Division of Pediatric Hematology and Oncology, Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.

Background: Low bone mass is common among adolescents with transfusion-dependent β-thalassemia despite adequate transfusion and iron chelation. However, there are few reports regarding bone mineral density (BMD) among adolescents with nontransfusion-dependent thalassemia (NTDT). Indeed, only BMD data in patients with nontransfusion-dependent (NTD) β-thalassemia intermedia have been reported. No previous study has investigated BMD among adolescents with NTD hemoglobin (Hb) E/β-thalassemia.

Objective: To determine the prevalence of low bone mass among adolescents with NTD Hb E/β-thalassemia and factors relating to low bone mass.

Methods: We investigated BMD of lumbar spine (L2-L4; BMDLS) and total body (BMDTB), as measured by dual-energy X-ray absorptiometry, in 22 adolescents (aged 13.2-20 years) with NTD Hb E/β-thalassemia.

Results: Low bone mass was found to be 18.2% and 22.7% at the lumbar spine (BMDLS Z-score adjusted for bone age and height age) and 13.6% and 9.1% at the total body (BMDTB Z-score adjusted for bone age and height age). Patients with mean Hb level <8 g/dl were more likely to have low bone mass (BMDLS and BMDTB Z-scores adjusted for bone age) compared to those with Hb level ≥ 8 g/dl. Mean Hb level correlated with BMDLS and BMDTB Z-scores adjusted for bone age.

Conclusion: We demonstrated that a low Hb level was associated with low bone mass among adolescents with NTD Hb E/β-thalassemia. A significant proportion of low bone mass among these patients highlights the importance of appropriate management, including red cell transfusion, vitamin D and calcium supplementation for improved long-term bone health.
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http://dx.doi.org/10.1002/pbc.26744DOI Listing
January 2018

Hepcidin suppression in β-thalassemia is associated with the down-regulation of atonal homolog 8.

Int J Hematol 2017 Aug 12;106(2):196-205. Epub 2017 Apr 12.

Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand.

Atonal homolog 8 (ATOH8) is defined as a positive regulator of hepcidin transcription, which links erythropoietic activity with iron-sensing molecules. In the present study, we investigated the association between hepcidin and ATOH8 expression in β-thalassemia. We found that inhibition of hepcidin expression in β-thalassemia is correlated with reduced ATOH8 expression. Hepatic hepcidin 1 (Hamp1) and Atoh8 mRNA expression were down-regulated in β-thalassemic mice. Hepcidin (HAMP) and ATOH8 mRNA expression were consistently suppressed in Huh7 cells cultured in medium supplemented with β-thalassemia patient serum. The Huh7 cells, which were transfected with ATOH8-FLAG expression plasmid and cultured in the supplemented medium, exhibited increased levels of ATOH8 mRNA, ATOH8-FLAG protein, pSMAD1,5,8, and HAMP mRNA. Interestingly, over-expression of ATOH8 reversed the effects of hepcidin suppression induced by the β-thalassemia patient sera. In conclusion, hepcidin suppression in β-thalassemia is associated with the down-regulation of ATOH8 in response to anemia. We, therefore, suggest that ATOH8 is an important transcriptional regulator of hepcidin in β-thalassemia.
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http://dx.doi.org/10.1007/s12185-017-2231-3DOI Listing
August 2017

Effects of iron overload, an iron chelator and a T-Type calcium channel blocker on cardiac mitochondrial biogenesis and mitochondrial dynamics in thalassemic mice.

Eur J Pharmacol 2017 Mar 10;799:118-127. Epub 2017 Feb 10.

Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand; Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand; Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, Thailand. Electronic address:

Although cardiac mitochondrial dysfunction is involved in the pathophysiology of iron-overload cardiomyopathy, the precise mechanisms of iron-induced mitochondrial dysfunction, and the roles of the iron chelator deferiprone and the T-type calcium channel blocker efonidipine on cardiac mitochondrial biogenesis in thalassemic mice are still unknown. β-thalassemic (HT) mice were fed with a normal diet (ND) or a high iron-diet (FE) for 90 days. Then, the FE-fed mice were treated with deferiprone (75mg/kg/day) or efonidipine (4mg/kg/day) for 30 days. The hearts were used to determine cardiac mitochondrial function, biogenesis, mitochondrial dynamics and protein expressions for oxidative phosphorylation (OXPHOS) and apoptosis. ND-fed HT mice had impaired heart rate variability (HRV), increased mitochondrial dynamic proteins and caspase-3, compared with ND-fed wild-type mice. Iron overload led to increased plasma non-transferrin bound iron, oxidative stress, and the impairments of HRV and left ventricular function, cardiac mitochondrial function and mitochondrial dynamics, and decreased complex IV in thalassemic mice. Our results suggested that deferiprone and efonidipine treatment showed similar benefit in attenuating cardiac iron deposit and oxidative stress, and improved cardiac mitochondrial function, leading to improved left ventricular function, without altering the cardiac mitochondrial biogenesis, and apoptosis proteins in iron-overload thalassemic mice.
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http://dx.doi.org/10.1016/j.ejphar.2017.02.015DOI Listing
March 2017

Heart Rate Variability for Early Detection of Cardiac Iron Deposition in Patients with Transfusion-Dependent Thalassemia.

PLoS One 2016 13;11(10):e0164300. Epub 2016 Oct 13.

Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.

Background: Iron overload cardiomyopathy remains the major cause of death in patients with transfusion-dependent thalassemia. Cardiac T2* magnetic resonance imaging is costly yet effective in detecting cardiac iron accumulation in the heart. Heart rate variability (HRV) has been used to evaluate cardiac autonomic function and is depressed in cases of thalassemia. We evaluated whether HRV could be used as an indicator for early identification of cardiac iron deposition.

Methods: One hundred and one patients with transfusion-dependent thalassemia were enrolled in this study. The correlation between recorded HRV and hemoglobin, non-transferrin bound iron (NTBI), serum ferritin and cardiac T2* were evaluated.

Results: The median age was 18 years (range 8-59 years). The patient group with a 5-year mean serum ferritin >5,000 ng/mL included significantly more homozygous β-thalassemia and splenectomized patients, had lower hemoglobin levels, and had more cardiac iron deposit than all other groups. Anemia strongly influenced all domains of HRV. After adjusting for anemia, neither serum ferritin nor NTBI impacted the HRV. However cardiac T2* was an independent predictor of HRV, even after adjusting for anemia. For receiver operative characteristic (ROC) curve analysis of cardiac T2* ≤20 ms, only mean ferritin in the last 12 months and the average of the standard deviation of all R-R intervals for all five-minute segments in the 24-hour recording were predictors for cardiac T2* ≤20 ms, with area under the ROC curve of 0.961 (p<0.0001) and 0.701 (p = 0.05), respectively.

Conclusions: Hemoglobin and cardiac T2* as significant predictors for HRV indicate that anemia and cardiac iron deposition result in cardiac autonomic imbalance. The mean ferritin in the last 12 months could be useful as the best indicator for further evaluation of cardiac risk. The ability of serum ferritin to predict cardiac risk is stronger than observed in other thalassemia cohorts. HRV might be a stronger predictor of cardiac iron in study populations with lower somatic iron burdens and greater prevalence of cardiac iron deposition.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0164300PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5063507PMC
May 2017

Combined Iron Chelator and Antioxidant Exerted Greater Efficacy on Cardioprotection Than Monotherapy in Iron-Overloaded Rats.

PLoS One 2016 18;11(7):e0159414. Epub 2016 Jul 18.

Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.

Background: Iron chelators are used to treat iron overload cardiomyopathy patients. However, a direct comparison of the benefits of three common iron chelators (deferoxamine (DFO), deferiprone (DFP) and deferasirox (DFX)) or an antioxidant (N-acetyl cysteine (NAC)) with a combined DFP and NAC treatments on left ventricular (LV) function with iron overload has not been investigated.

Methods And Findings: Male Wistar rats were fed with either a normal diet or a high iron diet (HFe group) for 4 months. After 2 months, the HFe-fed rats were divided into 6 groups to receive either: a vehicle, DFO (25 mg/kg/day), DFP (75 mg/kg/day), DFX (20 mg/kg/day), NAC (100 mg/kg/day) or the combined DFP and NAC for 2 months. Our results demonstrated that HFe rats had increased plasma non-transferrin bound iron (NTBI), malondialdehyde (MDA), cardiac iron and MDA levels and cardiac mitochondrial dysfunction, leading to LV dysfunction. Although DFO, DFP, DFX or NAC improved these parameters, leading to improved LV function, the combined DFP and NAC therapy caused greater improvement, leading to more extensively improved LV function.

Conclusions: The combined DFP and NAC treatment had greater efficacy than monotherapy in cardioprotection through the reduction of cardiac iron deposition and improved cardiac mitochondrial function in iron-overloaded rats.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0159414PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4948821PMC
July 2017

Iron distribution and histopathological study of the effects of deferoxamine and deferiprone in the kidneys of iron overloaded β-thalassemic mice.

Exp Toxicol Pathol 2016 Sep 9;68(8):427-34. Epub 2016 Jul 9.

Thalassemia Research Center, Institute of Molecular Biosciences, Mahidol University, Salaya Campus, Nakhon Pathom 73170, Thailand.

Renal glomerular and tubular dysfunctions have been reported with high prevalence in β-thalassemia. Iron toxicity is implicated in the kidney damage, which may be reversed by iron chelation therapy. To mimic heavy iron overload and evaluate the efficacy of iron chelators in the patients, iron dextran (180mg iron/mouse) was intraperitoneally (i.p.) injected in heterozygous β-globin knockout mice ((muβth-3/+), BKO) and wild type mice (C57BL/6J, WT) over a period of 2 weeks, followed by daily i.p. injection of deferoxamine (DFO) or deferiprone (L1) for 1 week. In BKO mice, iron preferentially accumulated in the proximal tubule with a grading score of 0-1 and increased to grade 3 after iron loading. In contrast, iron mainly deposited in the glomerulus and interstitial space in iron overloaded WT mice. Increased levels of kidney lipid peroxidation, glomerular and medullar damage and fibrosis in iron overloaded mice were reversed by treatment with iron chelators. L1 showed higher efficacy than DFO in reduction of glomerular iron, which was supported by a significantly decreased the amount of glomerular damage. Notably, DFO and L1 demonstrated a distinct pattern of iron distribution in the proximal tubule of BKO mice. In conclusion, chelation therapy has beneficial effects in iron-overloaded kidneys. However, the defect of kidney iron metabolism in thalassemia may be a determining factor of the treatment outcome in individual patients.
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http://dx.doi.org/10.1016/j.etp.2016.06.006DOI Listing
September 2016
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